Neurological disorders, in particular central nervous system (CNS) disorders, encompass numerous afflictions, including inter alia acute CNS injury (e.g., hypoxic-ischemic encephalopathies, stroke, traumatic brain injury, spinal cord injury, cerebral palsy), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, frontotemporal dementia), and a large number of central nervous system dysfunctions (e.g. depression, epilepsy, and schizophrenia).
Neonatal hypoxic-ischemic encephalopathy (HIE) is a neurological disorder that causes damage to cells in the brain in neonates due to inadequate oxygen supply. Brain hypoxia and ischemia due to systemic hypoxemia and reduced cerebral blood flow (CBF) are primary reasons leading to neonatal HIE accompanied by gray and white matter injuries occurring in neonates. Neonatal HIE may cause death in the newborn period or result in what is later recognized as developmental delay, mental retardation, or cerebral palsy (CP). Even though different therapeutic strategies have been developed recently, neonatal HIE remains a serious condition that causes significant mortality and morbidity in near-term and term newborns and therefore, it remains a challenge for perinatal medicine.
Over the past several years, a rat model of hypoxic-ischemic brain damage became the most employed model in perinatal medicine. At post-natal day 7 (P7; day of birth=P1), the rats brain is histologically similar to that of a 32- to 34-week gestation human fetus or newborn infant, i.e., cerebral cortical neuronal layering is complete, the germinal matrix is involuting, and white matter as yet has undergone little myelination. In order to produce hypoxic-ischemic brain damage in the 7-day-old rat pups, they undergo unilateral common carotid artery ligation followed by systemic hypoxia produced by the inhalation of 8% oxygen/balance nitrogen, at constant temperature (37° C.) (Vanucci et al. 2005. Dev Neurosci, vol. 27, 81-86).
The rat model has proven to provide important information regarding underlying mechanisms of perinatal hypoxic-ischemic brain damage and how tissue injury can be prevented or minimized through therapeutic intervention. In particular, physiologic and therapeutic manipulations have been applied to the immature rat model of perinatal hypoxic-ischemic brain damage in order to evaluate potential treatments, including hypothermia, xenon treatment and erythropoietin administration.
Promising neuroprotective agents include antiepileptic drugs, erythropoietin, melatonin and xenon. Data from animal models of asphyxia further suggest that neurologic outcome after HIE can be improved by adding adjuvant therapies to hypothermia, beginning in the hours to days after insult. These promising treatments need now to be assessed in clinical trials. Phase 1-2 clinical studies using biomarker outcomes, e.g., phosphorous magnetic resonance spectroscopy, and involving small number of infants are key to assess safety and potential efficacy before new treatments are taken to pragmatic trials. Phase 1-2 trials of xenon and erythropoietin are already planned or underway.
Preterm birth is a major risk factor for diffuse white matter injury (dWMI) leading to neurological disabilities including cerebral palsy, mental retardation, visual and hearing deficiency, learning-related problems, deficits in visuospatial and visuomotor skills that involve special cares. In the preterm infant, dWMI include, among other pathological conditions, cystic and non cystic periventricular leukomlacia (PVL).
Pathophysiological mechanisms of dWMI include infection, inflammation, hypoxia-ischemia and oxidative stress. Experimental studies have suggested a sensitizing effect of systemic inflammation that makes the perinatal brain more vulnerable to further insults. A mouse model of inflammation-induced dWMI, mimicking the histopathological, radiological and clinical aspects of the human preterm dWMI has been recently developed (Favrais et al 2011).
There is still no specific treatment against PVL and its consequences, except antenatal magnesium sulphate therapy given to women at risk of preterm birth that substantially reduced the risk of motor disorders in childhood. Promising neuroprotective agents against brain lesions in the preterm infant include erythropoietin, melatonin. Phase 2-3 trials of prenatal administration of melatonin for women at risk for preterm birth and postnatal administration of erythropoietin are underway.
Therapies for neurological disorders, in particular CNS injuries or neurodegenerative diseases, may center on protecting against brain or spinal cord damage or restoring nerve cell activity, e.g., through the use of neurotrophic factors. Neurothrophic factors, such as e.g., epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α), are polypeptides that variously support the survival, proliferation, differentiation, size, and function of nerve cells. Treatment of neurological disorders may also encompass the administration of stem cells to replace those neural cells lost by natural cell death, injury or disease.
A problem encountered with the administration of such neurotrophic factors or stem cells is the blood-brain barrier, which may impede their transfer from the blood flow into the CNS. Therefore, treatments often require the direct application of a neurotrophic factor or infusion of stem cells to a site of injury or damage in the CNS in a subject in need of such treatment.
Given the paucity of successful treatments for neurological disorders in general, there remains a need for additional therapeutic agents and methods, that preferably do not rely on invasive intracranial procedures or substances with improved blood-brain barrier passage.